Investigating the role of Copy Number Variants in Specific Language Impairment and identification of new candidate genes

Specific language impairment (SLI) is a complex neurodevelopmental disorder defined as an unexpected failure to develop normal language abilities for no obvious reason. Copy number variants (CNVs) are an important source of variation in the susceptibility to neuropsychiatric disorders. Therefore, a CNV study within SLI families was performed to investigate the role of structural variants in SLI. Among the identified CNVs, we focused on CNVs on chromosome 15q11-q13, recurrently observed in neuropsychiatric conditions, and a homozygous exonic microdeletion in ZNF277. Since this microdeletion falls within the AUTS1 locus, a region linked to autism spectrum disorders (ASD), we investigated a potential role of ZNF277 in SLI and ASD. Frequency data and expression analysis of the ZNF277 microdeletion suggested that this variant may contribute to the risk of language impairments in a complex manner, that is independent of the autism risk previously described in this region. Moreover, we identified an affected individual with a dihydropyrimidine dehydrogenase (DPD) deficiency, caused by compound heterozygosity of two deleterious variants in the gene DPYD. Since DPYD represents a good candidate gene for both SLI and ASD, we investigated its involvement in the susceptibility to these two disorders, focusing on the splicing variant rs3918290, the most common mutation in the DPD deficiency. We observed a higher frequency of rs3918290 in SLI cases (1.2%), compared to controls (~0.6%), while no difference was observed in a large ASD cohort. DPYD mutation screening in 4 SLI and 7 ASD families carrying the splicing variant identified six known missense changes and a novel variant in the promoter region. These data suggest that the combined effect of the mutations identified in affected individuals may lead to an altered DPD activity and that rare variants in DPYD might contribute to a minority of cases, in conjunction with other genetic or non-genetic factors.

Cognition in context: Evidence on affordances and verbal language

This thesis investigated affordances and verbal language to demonstrate the flexibility of embodied simulation processes. Starting from the assumption that both object/action understanding and language comprehension are tied to the context in which they take place, six studies clarified the factors that modulate simulation. The studies in chapter 4 and 5 investigated affordance activation in complex scenes, revealing the strong influence of the visual context, which included either objects and actions, on compatibility effects. The study in chapter 6 compared the simulation triggered by visual objects and objects names, showing differences depending on the kind of materials processed. The study in chapter 7 tested the predictions of the WAT theory, confirming that the different contexts in which words are acquired lead to the difference typically observed in the literature between concrete and abstract words. The study in chapter 8 on the grounding of abstract concepts tested the mapping of temporal contents on the spatial frame of reference of the mental timeline, showing that metaphoric congruency effects are not automatic, but flexibly mediated by the context determined by the goals of different tasks. The study in chapter 9 investigated the role of iconicity in verbal language, showing sound-to-shape correspondences when every-day object figures, result that validated the reality of sound-symbolism in ecological contexts. On the whole, this evidence favors embodied views of cognition, and supports the hypothesis of a high flexibility of simulation processes. The reported conceptual effects confirm that the context plays a crucial role in affordances emergence, metaphoric mappings activation and language grounding. In conclusion, this thesis highlights that in an embodied perspective cognition is necessarily situated and anchored to a specific context, as it is sustained by the existence of a specific body immersed in a specific environment.